1. Field of the Invention
The present invention generally relates to medical treatment. Particularly, the present invention relates to a method for preventing or treating the development of opiate tolerance and dependence using a blocking reagent for ephrinB-EphB signaling.
2. Description of the Related Art
Opioid drugs are used and abused for their analgesic and rewarding properties. Repeated use of opioids such as morphine for relief of chronic pain can lead to opiate tolerance and dependence. Mechanisms of opiate tolerance are very complex and involve factors at the levels of the drug receptor, the cell, and neural networks. Roles of diverse neurotransmitter and receptor systems and intracellular signaling proteins in acute and chronic opioid actions have been demonstrated (Bailey & Connor, 2005; Bohn et al, 2000; Collier, 1980; King et al, 2001; Muscoli et al, 2007; Pasternak, 2007; Roerig et al, 1984; Zachariou et al, 2003). The most intensively studied system is the glutamate/NMDA receptor/NO cascade (Ben-Eliyahu et al, 1992; Inoue et al, 2003; Inturrisi, 2002; Kolesnikov et al, 1998; Kolesnikov et al, 1993; Kolesnikov et al, 1992; Muscoli et al, 2007; Pasternak, 2007; Pasternak & Kolesnikov, 2005; Trujillo & Akil, 1991). Adaptive changes following chronic opioid exposure that might underlie physical dependence by altering neuronal excitability and synaptic transmission include a withdrawal-induced rebound increase in cAMP levels and in expression of the cAMP response element binding protein (CREB) (Barrot et al, 2002; Nestler, 2001; Shaw-Lutchman et al, 2002) and MAPKs (Sweatt, 2004). The capacity of agonists to recruit various μ-opioid receptor (MOR) regulatory events has recently been suggested to be a major determinant of their propensity to induce both tolerance and dependence (Bailey & Connor, 2005). Despite decades of investigation, the specific cellular and molecular mechanisms underlying opioid tolerance and withdrawal-induced pain enhancement remain elusive. One general possibility is that repetitive or prolonged MOR activation may elicit neuronal alterations that recapitulate events during development (Chen et al, 2007) including the promotion of synapse formation. It is of clinical important to determine the mechanisms underlying tolerance and physical dependence, and to develop medications that can prevent, minimize, or reverse opioid tolerance and dependence.
Eph-receptors constitute the largest subfamily of receptor tyrosine kinases (RTKs), and they play vital roles in transmitting external signals to the inside of many types of cells. In humans there are 13 Eph-receptor genes, divided into an A-subclass (EphA1-EphA8) and a B-subclass (EphB1-EphB4, EphB6). Their ligands, the ephrins, are also divided into two subclasses: ephrinA1-ephrinA5 and ephrinB1-ephrinB3. A-type receptors typically bind to most or all A-type ligands, and B-type receptors bind to most or all B-type ligands (Kullander & Klein, 2002). Eph RTKs and ephrins are involved in tissue-border formation, cell migration, and axon guidance during development of the nervous system (Krull et al, 1997; Wang & Anderson, 1997; Wilkinson, 2000; Wilkinson, 2001). EphB receptors can also regulate the development and remodeling of glutamatergic synaptic connections and their plasticity in adult nervous system by interaction with NMDA receptors (NMDARs) (Chen et al, 2007; Dalva et al, 2000; Grunwald et al, 2004; Grunwald et al, 2001; Henderson et al, 2001; Takasu et al, 2002). NMDARs containing both NR1 and NR2 subunits have an established role in neural plasticity and are fundamental mediators of expression, development and maintenance of opiate tolerance, dependence and withdrawal (Bailey & Connor, 2005; Herman et al, 1995; Mao, 1999; Mao et al, 2002; Mayer et al, 1999; Noda & Nabeshima, 2004; Zhu & Barr, 2001). The opiate systems interact with NMDARs such that MOR activation results in Ca2+ influx through the NMDAR ion-channel complex. The subsequent activation of various Ca2+-dependent enzymes, such as Ca2+/calmodulin-dependent kinase (CaMK) (Fan et al, 1999; Hamdy et al, 2004; Liang et al, 2004; Lou et al, 1999; Lu et al, 2000) and ERK (Ren et al, 2004; Schulz & Hollt, 1998) play a central role in the induction of persistent opioid effects (Noda & Nabeshima, 2004).
Recent studies have further demonstrated that peripheral inflammation and/or nerve injury enhances ephrinB-EphB receptor signaling (Kobayashi et al, 2007; Song et al, 2008a), and such signaling may contribute to inflammatory and neuropathic pain by altering neural excitability and synaptic transmission via interaction with NMDARs in the spinal cord (SC) (Battaglia et al, 2003; Song et al, 2008a; Song et al, 2008b). Several lines of evidence indicate that the spinal dorsal horn (DH), the first central relay station for processing nociceptive information, is an important site in the development of opioid dependence and withdrawal (Jhamandas et al, 1996; Mao et al, 2002; Marshall & Buccafusco, 1985; Mayer et al, 1999; Muscoli et al, 2007; Rohde & Basbaum, 1998; Rohde et al, 1996; Rohde et al, 1997; Trang et al, 2003).
There is apparently a need for an effective method for preventing, minimizing or reversing opiate tolerance and dependence. The present invention fulfills this long-standing need.